It has been proposed that compounds, such as peptides, peptide mimetics, and oligonucleotides, or analogs or derivatives thereof, can be used as potential therapeutic agents. However, problems have been encountered in administering such compounds to a subject. For example, proteases and endonucleases present throughout the body digest such compounds, severely decreasing their biological activity. Other problems involve the elicitation of an immune response against the compound resulting in the degradation and inactivation of such compounds, and rapid renal clearance, particularly if the therapeutic agent has a low molecular weight. Hence, in order'to be effective, such therapeutic agents must be administered frequently, and parenterally rather than orally. An example of such a therapeutic agent is insulin, which is typically injected several times daily by diabetics.
In efforts to overcome these problems, researchers have attempted to modify chemically such therapeutic agents in order to manipulate their pharmacologic properties.sup.1, and perhaps enable them to survive longer in vivo before being degraded and removed from the blood stream. For example, one method of chemically modifying therapeutics is to append water-soluble polymer chains, such as polyethylene glycol (PEG), to the therapeutic agent.sup.2. Researchers have designed a PEG-lysine copolymer having multiple attachment sites.sup.3, and have conjugated the copolymer to low molecular weight therapeutic agents. However, such modifications have inherent limitations. For example, they frequently interfere with the bioavailability of the therapeutic. Consequently, if the target for a therapeutic agent is intracellular, and the modification of the therapeutic prevents its crossing of the cell membrane, then the bioavailability of the therapeutic agent is reduced due to the chemical modification.
Another limitation to attaching a water-soluble polymer to a therapeutic agent involves modulating the biological activity of the therapeutic agent in a deleterious manner. For example, if the modification of the therapeutic agent alters its three dimensional structure, then its ability to bind a receptor site it was designed to bind can be decreased, resulting in a decrease of activity.
Hence, what is needed is a carrier of a therapeutic agent that reduces the chance of an elicitation of an immune response against the therapeutic agent.
Moreover, what is needed is a carrier that protects therapeutic agents from protease/peptidase/nuclease degradation in vivo, thereby eliminating the need for repetitive administration of the therapeutic agent.
In addition, what is needed is a carrier of a therapeutic agent that enhances cellular transmembrane delivery of the therapeutic agent.
Also, what is needed is a carrier of a therapeutic agent that does not release the therapeutic agent until the carrier has crossed the cell membrane, and once inside the cell, the carrier can release the therapeutic agent in a biologically active state.
What is also needed is a carrier of a therapeutic agent that does not interfere with the bioavailability of the therapeutic agent.